Diethyl Acetonylphosphonate

[1067-71-6]  · C7H15O4P  · Diethyl Acetonylphosphonate  · (MW 194.17)

(Horner-Emmons reagent for the conversion of aldehydes and ketones to a,b-unsaturated methyl ketones;1 can react via the corresponding derived metallic dianions to yield other b-ketophosphonates2)

Alternate Name: diethyl acetylmethylphosphonate.

Physical Data: bp 126 °C/9 mmHg; d 1.010 g cm-3; nD20 1.4330; d 31P 93.7 ppm (from P4O6 as reference),3 -20 ppm (from 85% H3PO4 as external reference).4

Solubility: sol THF, ether, dichloromethane, chloroform.

Form Supplied in: colorless liquid.

Horner-Emmons Reagent.

Diethyl acetonylphosphonate is a very efficient reagent for the preparation of a variety of a,b-unsaturated methyl ketones via the Horner-Emmons modification5 of the Wittig reaction and has the advantage over the equivalent Wittig ylide of much greater reactivity.1 The corresponding derived sodium anion that realizes the carbonyl alkenation is usually obtained in aprotic medium with a limited range of solvents and bases, such as Sodium Hydride/THF, NaH/DME,6 or Sodium Hydroxide/DMF.7

Excellent yields are obtained from aldehydes, often leading to exclusive trans stereochemistry for the a,b-unsaturated ketones formed (eq 1).8 The lower electrophilic behavior of ketones combined with the increased steric hindrance results in lower yields,6 and therefore allows, in the case of keto aldehydes, a chemoselective aldehyde alkenation (eq 2).9

Often the carbonyl alkenation with diethyl acetonylphosphonate is part of a multistep synthesis of natural or bioactive products (eqs 3-5).10-12

Diethyl acetonylphosphonate has also been used in an annulation sequence for building a cyclohexadienone ring onto a cyclic ketone (eq 6).13

The Horner-Emmons reaction with diethyl acetonylphosphonate can be carried out in a protic solvent such as ethanol, with Potassium Hydroxide14 or Potassium Carbonate15 as base. Recently, two-phase liquid-liquid or solid-liquid procedures have been described and often represent a significative improvement for the Horner-Emmons reaction. Typical results are obtained in water, in the absence of organic solvents, using 6 M potassium carbonate as base (eq 7).16

Under similar heterogeneous conditions, an aqueous solution of glutaraldehyde gives 1-acetyl-1-cyclohexen-6-ol (eq 8).17

a-Labeled a,b-unsaturated methyl ketones (%D > 95%) can also be prepared with this procedure in the presence of 6 M K2CO3 in deuterium oxide solution at rt (eq 9).18

Microcrystalline Barium Hydroxide C200 [Ba(OH)2.0.8H2O, or Ba(OH)2.0.2H2O] has been used in very efficient solid-liquid Horner-Emmons reactions with b-ketophosphonates.19 Under these conditions, Claisen-Schmidt and Horner-Emmons syntheses of acyclic enones using, respectively, acetone and diethyl acetonylphosphonate as reagents have been compared. The comparison shows that the Horner-Emmons reaction is more efficient and selective, while the Claisen-Schmidt condensation leads to a mixture of enone and dienone. The (E) stereoselectivity of the reaction is the same in both cases (eq 10).20

Preparation of Other b-Ketophosphonates.

a-Substituted or g-substituted alkyl b-ketophosphonates can be prepared from, respectively, the monoanion21 or the dianion of diethyl acetonylphosphonate. Prior a-alkylation of the sodium enolate, before the carbonyl alkenation step, is often employed (eq 11).22

Prior a-alkylation is also required for other subsequent reactions as, for instance, an intramolecular aza-Wittig (Staudinger) reaction (eq 12).23

If desired, the dianion generated from diethyl acetonylphosphonate by successive treatment with NaH and n-Butyllithium can be alkylated at the g-position with homoallyl bromide to yield diethyl 2-oxo-6-hepten-1-ylphosphonate (eq 13).2a Other examples of this g-alkylation have been described with the dianion derived from diethyl acetonylphosphonate.2b

The Derived Metallic Dianion as Reagent.

The dianion derived from diethyl acetonylphosphonate gives g-hydroxyalkylation with carbonyl compounds. After dehydration, the resulting 2-oxo-3-alkenylphosphonates serve as heterodienes in thermal reactions with vinyl ethers, leading ultimately to 5-substituted 2-phosphinyl-2-cyclohexen-1-ones.24 Formed on the surface of solid K2CO3/MeOH, in the presence of Iodine, the dianion can be exclusively g-iodinated and gives in situ a novel ambident iodinated dianion where the two CH groups have approximately equivalent reactivity. Aromatic aldehydes react with this last intermediate in a simultaneous Horner-Emmons and Darzens reaction to yield epoxy enones (eq 14).25

The dianion can be also formylated or acylated with ethyl esters or acyl chlorides in the g-position to yield diethyl 2,4-dioxoalkylphosphonates. The deprotonation is carried out with NaH/THF at 20 °C with 1 equiv of sodium hydride followed by 2 equiv of Lithium Diisopropylamide at 0 °C. The excess of LDA is essential for a quantitative formation of the dianion because of proton transfer from the acylated product (eq 15).26

Miscellaneous Reactions.

Diethyl acetonylphosphonate can be used to prepare indolylphosphonates via a Fischer cyclization.27 It also undergoes reductive amination in the presence of an amine and Sodium Cyanoborohydride in MeOH at pH 7-7.5 to yield the corresponding b-amino phosphonates (eq 16).28

Strecker reaction leads to phosphonate analogs of a-methylaspartic acid.29 Diethyl nitromethylphosphonate is obtained from the reaction between diethyl acetonylphosphonate and HNO3/Ac2O in 70% yield.30

1. (a) Cadogan, J. I. G. Organophosphorus Reagents in Organic Synthesis; Academic: New York, 1979. (b) Wadsworth, W. S., Jr. OR 1977, 25, 73. (c) Sturtz, G. Colloques Nationaux du CNRS: Composés Organiques du Phosphore, Toulouse, 1965; CNRS: Paris, 1966; p 135. (c) Sturtz, G. Colloques Internationaux du CNRS: Chimie Organique du Phosphore, Paris, 1969; CNRS: Paris, 1970; p 217.
2. (a) Mikolajczyk, M.; Zurawinski, R.; Kielbasinski, P TL 1989, 30, 1143. (b) Grieco, P. A.; Pogonowski, C. S. JACS 1973, 95, 3071.
3. Mavel, G.; Mankowski-Favelier, R.; Sturtz, G. J. Chim. Phys. 1967, 64, 1686.
4. Lenzi, M.; Sturtz, G.; Lavielle, G. CR(C) 1967, 264, 1425.
5. Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. CB 1959, 92, 2499.
6. Normant, H.; Sturtz, G. CR 1963, 256, 1800.
7. Henrick, C. A.; Willy, W. E.; McKean, D. R.; Baggiolini, E.; Siddall, J. B. JOC 1975, 40, 8.
8. Schreiber, S. L.; Meyers, H. V.; Wiberg, K. B. JACS 1986, 108, 8274.
9. Kovalev, B. G.; Al'tmark, E. M. ZOR 1972, 8, 1582.
10. Konno, K.; Hashimoto, K.; Ohfune, Y.; Shirahama, H.; Matsumoto, T. TL 1986, 27, 607.
11. Demole, E.; Demole, C.; Enggist, P. HCA 1976, 59, 737.
12. Wannagat, U.; Müstedt, R.; Harder, U. LA 1985, 950.
13. Thangaraj, K.; Srinivasan, P. C.; Swaminathan, S. S 1982, 855.
14. (a) Bonjoch, J.; Casamitjana, N.; Bosch, J. T 1988, 44, 1735. (b) Corey, E. J.; Gorzynski-Smith, J. JACS 1979, 101, 1038.
15. Mikolajczyk, H.; Balczewski, P. S 1987, 659.
16. Villieras, J.; Rambaud, M. S 1983, 300.
17. Graff, M.; Al Dilaimi, A.; Seguineau, P.; Rambaud, M.; Villieras, J. TL 1986, 27, 1577.
18. Seguineau, P.; Villieras, J. TL 1988, 29, 477.
19. Alvarez-Ibarra, C.; Arias, S.; Fernández, M. J.; Sinisterra, J. V. JCS(P2) 1989, 503.
20. Alvarez-Ibarra, C.; Arias-Pérez, M. S.; Fernández, M. J.; Serrano, D.; Sinisterra, V. JCR(S) 1992, 326.
21. Diana, G. D.; Zalay, E. S.; Salvador, U. J.; Pancic, F.; Steinberg, B. JMC 1984, 27, 691.
22. Miller, D. B.; Raychaudhuri, S. R.; Avasthi, K.; Lal, K.; Levison, B.; Salomon, R. G. JOC 1990, 55, 3164.
23. Khoukhi, M.; Vaultier, M.; Carrié, R. TL 1986, 27, 1031.
24. Wada, E.; Kanemasa, S.; Tsuge, O. BCJ 1989, 62, 860.
25. Iman, M.; Chenault, J. S 1989, 124.
26. Fouqué, D.; About-Jaudet, E.; Collignon, N.; Savignac, P. SC 1992, 22, 219.
27. Haelters, J. P.; Corbel, B.; Sturtz, G. CR(C) 1985, 301, 697.
28. Varlet, J. M.; Collignon, N.; Savignac, P. T 1981, 37, 3713.
29. Gruszecka, E.; Soroka, M.; Mastalerz, P. Pol. J. Chem. 1979, 53, 2327 (CA 1980, 93, 8479d).
30. Neimysheva, A. A.; Muratov, S. S.; Smirnov, E. V.; Solntseva, L. M. ZOB 1976, 46, 940.

Philippe Coutrot & Claude Grison

Université de Nancy I, Vandoeuvre les Nancy, France

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